In Reply:—

The question raised by Dr. Wang is very important on a scientific basis as well as on a basis of clinical relevancy of our study. 1 

It is well known that vasoconstrictors such as epinephrine, phenylephrine, and clonidine prolong the duration of action of various local anesthetics after subarachnoid administration. The mechanism(s) for this prolongation involve both vasoconstriction and antinociception from α2-stimulation. As Dr. Wang pointed out, vasoconstrictive response to α2-adrenergic stimulation could be influenced by release of nitric oxide. Coughlan et al . 2reported in an in vitro  study that Nw-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, was associated with exaggerated constrictor response to dexmedetomidine in coronary, but not in cerebral arteries. In vivo,  McPherson et al . 3demonstrated that inhibition of nitric oxide synthase by systemic Nw-nitro-L-arginine methyl ester did not affect dexmedetomidine-induced decreases in cerebral blood flow. In addition, we also found that pretreatment with Nw-nitro-L-arginine methyl ester failed to influence the response of cerebral pial arterioles to 10−3m dexmedetomidine in the same experimental design. 4Further oppositely, it has been reported that in isolated rat’s cerebral artery, dilation produced by α2- agonist was blocked with inhibition of nitric oxide synthase. 5Because we did not examine the effect of activation of endothelial α2-adrenoceptors on vascular reactivity of the spinal microcirculation via  production of nitric oxide, we cannot exclude the possibility that the change of endothelial function attributable to different physiologic and pathologic states may alter the vasoconstrictive effect of α2-agonists and the effectiveness as local anesthetic additives.

In addition, we previously reported that the pial vascular effects of α2-agonists were modulated via  potassium channel activation using a cranial window preparation. The vasoconstrictive effects of dexmedetomidine and clonidine seem to be mediate via  activation of α2-adrenoceptors, and partly counterbalanced vasodilation via  activation of adenosine triphosphate sensitive potassium channels. 4,6Moreover, we also reported that local anesthetics such as bupivacaine and ropivacaine per se  affect spinal pial vessels, even to the different direction, affecting the duration during spinal anesthesia. 7 

Therefore, it is possible that not only nitric oxide, but also other possible vasoactive condition including adenosine triphosphate sensitive potassium channels activation and concomitantly used local anesthetics could modulate the vasoconstrictive effects of α2-agonists.

Iida H, Ohata H, Iida M, Watanabe Y, Dohi S: Direct effects of α1- and α2-adrenergic agonists on spinal and cerebral pial vessels in dogs. A nesthesiology 1999; 91:479–85
Coughlan MG, Lee JG, Bosnjak ZJ, Schmeling WT, Kampine JP, Wartier DC: Direct coronary and cerebral vascular responses to dexmedetomidine. A nesthesiology 1992; 77:998–1006
McPherson RW, Kirsch JR, Traystman RJ: Inhibition of nitric oxide synthase does not affect α2-adrenergic-mediated cerebral vasoconstriction. Anesth Analg 1994; 78:67–72
Ishiyama T, Dohi S, Iida H, Watanabe Y, Shimonaka H: Mechanisms of dexmedetomidine-induced cerebrovascular effects in canine in vivo  experiments. Anesth Analg 1995; 81:1208–15
Bryan RM Jr, Eichler MY, Swafford MWG, Johnson TD, Suresh MS, Childres WF: Stimulation of α2-adrenoceptors dilates the rat middle cerebral artery. A nesthesiology 1996; 85:82–90
Ishiyama T, Dohi S, Iida H: The vascular effects of topical and intravenous α2-adrenoceptor agonist clonidine on canine pial microcirculation. Anesth Analg 1998; 86:766–72
Iida H, Watanabe Y, Dohi S, Ishiyama T: Direct effects of ropivacaine and bupivacaine on spinal pial vessels in canine. Assessment with closed spinal window technique. A nesthesiology 1997; 87:75–81